Although several approaches to overcome difficult bile duct cannulation and gain free biliary access have been popularized, the use of gastrointestinal peptide hormonal agents such as sincalide, a cholecystokinin agonist, as an alternative method has not been evaluated. I have carried out a prospective, nonrandomized assessment of the use of sincalide for diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). Overall, sincalide was used in 23% (32/136) of ERCPs in 26.6% (29/109) patients. Sincalide was successfully used to (a) obtain a cholangiogram after initial failure using only a standard catheter in 12 of 19 patients; (b) precisely locate the papilla and bile duct orifice in five of five patients; (c) locate the bile duct opening to obtain a cholangiogram and free cannulation during needle-knife papillotomy or weeks later in five of seven and three of three patients, respectively; and (d) gain free access (deep cannulation) to the bile duct after a cholangiogram in 5 of 10 patients. The selected use of sincalide appears to enhance the success of diagnostic and therapeutic ERCP; however, perseverance alone may account for some of this success. Controlled, randomized trials comparing sincalide or nothing, sincalide or a sphincterotome, or sincalide or glide or guide wire in patients in whom initial attempts to obtain a cholangiogram are unsuccessful are warranted.